Identification of Genes Selectively Regulated by IFNs in Endothelial Cells

Abstract

IFNs are highly pleiotropic cytokines also endowed with marked antiangiogenic activity. In this study, the mRNA expression profiles of endothelial cells (EC) exposed in vitro to IFN-α, IFN-β, or IFN-γ were determined. We found that in HUVEC as well as in other EC types 175 genes were up-regulated (>2-fold increase) by IFNs, including genes involved in the host response to RNA viruses, inflammation, and apoptosis. Interestingly, 41 genes showed a >5-fold higher induction by IFN-α in EC compared with human fibroblasts; among them, the gene encoding the angiostatic chemokine CXCL11 was selectively induced by IFN-α in EC along with other genes associated with angiogenesis regulation, including CXCL10, TRAIL, and guanylate-binding protein 1. These transcriptional changes were confirmed and extended by quantitative PCR analysis and ELISA; whereas IFN-α and IFN-β exerted virtually identical effects on transcriptome modulation, a differential gene regulation by type I and type II IFN emerged, especially as far as quantitative aspects were concerned. In vivo, IFN-α-producing tumors overexpressed murine CXCL10 and CXCL11, guanylate-binding protein 1, and TRAIL, with evidence of CXCL11 production by tumor-associated EC. Overall, these findings improve our understanding of the antiangiogenic effects of IFNs by showing that these cytokines trigger an antiangiogenic transcriptional program in EC. Moreover, we suggest that quantitative differences in the magnitude of the transcriptional activation of IFN-responsive genes could form the basis for cell-specific transcriptional signatures.

Essential Impact of NF-κB Signaling on the H5N1 Influenza A Virus-Induced Transcriptome

“…The induced profile indeed shows a broad overlap to mRNA profiles from IFN-␤-stimulated HUVEC (51). However, there are certain published ISGs which were not induced upon IFN type I stimulation in the study by Indraccolo et al, (51) but are expressed in the case of influenza A virus infection (e.g., IP-10, IP9, Mig, RAN-TES). A recent study underlined that certain genes, classified as ISGs, are expressed independently of, although often in parallel to type I IFNs (52).…”

Transcriptome analysis of peripheral blood mononuclear cells in human subjects following a 36 h fast provides evidence of effects on genes regulating inflammation, apoptosis and energy metabolism

“…The remaining 2 genes (interferon, alpha-inducible protein 27 (IFI27) and ubiquitin-specific peptidase 18 (USP18)] from the set of seven had not been included in the statistical analysis as they failed to meet the criteria set for expressed genes. A number of other genes shown previously to be upregulated by type 1 IFN in endothelial cells were also present in the list of genes significantly associated with BMI (Indraccolo et al 2007). These were OASL, OAS1, OAS2, OAS3, RTP4/IFRG28, HERC6, ISG15, SP110 and PSMB9 and the expression of each of these also exhibited an apparent positive association with BMI.…”

Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers

“…The occurrence of digital ulcers is believed to be a reflection of an imbalanced angiogenesis. As type I IFNs are known to display antiangiogeneic activity, 19 it is tempting to speculate on a role for increased levels of type I IFNs in the process of digital ulcer formation.…”